The overall goal of this research program is to elucidate the role of blood rheology as a determinant of microvascular function in health and disease. To this end, techniques of intravital microscopy will be applied to evaluate the extent to which red blood cell (RBC) deformability and aggregation, and white blood cell (WBC) deformability and adhesion to the endothelium, affect the resistance to blood flow in vessels ranging from the true capillaries, to the arterioles and venules which serve them. Quantitative indices of microvascular function will be derived from direct in situ measurements of hemodynamic variables in exteriorized tissues such as the mesentery, omentum and cremaster muscle. Specific aims are to elucidate the relationship between blood flow and blood cell mechanical properties within individual microvessels, at branch points throughout the microvascular network and regionally throughout the succession of major microvascular divisions. A major emphasis of the research will be to elucidate microvascular function in the low flow state induced by either mechanical intervention of the arterial inflow or hemorrhagic hypotension. Specific studies on RBCs will examine red cell sequestration and entrapment in the low flow state, in response to the induction of red cell aggregation by administration of high molecular weight dextrans or by reduction of red cell deformability by exchange transfusion with hardened RBCs. Parallel stUdies on WBCs will be performed to evaluate their distribution throughout the microvascular network and their sequestration in light of their deformability and adhesiveness to the endothelium. The effects of in situ activation of WBCS, resulting from chemoattractants or prolonged ischemia, will be studied. Particular attention will be given to the preferential adhesion of WBCs to postcapillary venular endothelium in light of the relationship between WBC deformability, adhesiveness, and hemodynamic forces (shear stresses) which tend to sweep the WBC from the venular wall. A major goal will be to delineate the relative roles of entrapment of WBCs in the capillary orifice versus WBC-endothelium adhesion in affecting recovery from ischemic episodes. Mathematical modelling and computer simulations will also be performed to elucidate the relative contributions of blood cell deformability and cell-cell interaction in affecting microvascular function. It is anticipated that the results of these studies will provide greater insight into the role of the mechanical and biochemical properties of blood cells in affecting microvascular function which will aid in the clinical management of a variety pathophysiological states such as anemia, polycythemia, the low flow state, shock, inflammation and blood cell disorders, to name a few.